Sudhagar S, PhD.,
Sudhagar S, PhD.,
Associate Professor
Department of Biotechnology
Associate Professor
Department of Biotechnology
National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati
Email: sudhagar@niperguwahati.in
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Department of Biotechnology
Biosketch
Biosketch
A passionate teacher and academic researcher with over 13+ years of post-PhD experience in cancer biology and signal transduction, with a “strong belief in original ideas” to understand complex biological questions. With subject expertise in Biochemistry, Cell & Molecular Biology, my research group is trying to understand the cancer cell adaptation to its microenvironmental stress and the development of acquired drug resistance through studying organelle dynamics, metabolism and signal transduction with the support of various Extramural Research Grants.
GPER inhibits BCAA metabolism
Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling, energy balance and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite BCAA’s importance in human health, our understanding of its metabolic regulation is limited. In our recent publication in FEBS letters, we presented evidence that G-protein coupled estrogen receptor (GPER) activation inhibits key BCAA metabolic regulatory enzyme, branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in Leucine, Isoleucine and Valine accumulation in the cells. Interestingly, GPER did not alter the BCKDK and PPM1K levels but activated the MAPK signalling and using gene silencing, we have identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling.
The GPER-mediated regulation of BCAA metabolism is significant because both estrogen and BCAA have a significant impact on normal physiology and are directly linked to several disease conditions. Funding: ICMR Ad-Hoc (2023-26)
Tamoxifen Modulates Mitochondrial Dynamics and ER stress during metabolic stress
© SS Lab
The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Here, we presented evidence that tamoxifen supports breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK Signaling. Tamoxifen enhances mitochondrial fusion under nutrition‐deprived conditions by suppressing Drp1 ser616 phosphorylation and upregulating Mfn1 levels. Tamoxifen‐induced mitochondrial fusion is mediated by the activation of AMPK, as evidenced by the pharmacological inhibition of AMPK reverse mitochondrial fusion. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates nutrition deprivation-induced endoplasmic reticulum stress by enhancing selective ER-phagy and specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion and ER-phagy by regulating stress kinase Signaling under nutrition deprivation conditions.
Funding: ICMR NE Seed Grant (2020-22)
Thioridazine induces phospholipid accumulation and necroptosis in parental and tamoxifen-resistant breast cancer cells.
Tamoxifen resistance presents a significant therapeutic challenge in breast cancer, largely attributed to tumour heterogeneity. Drug repurposing offers a viable strategy to overcome this limitation. We evaluated the antipsychotic Thioridazine for its efficacy against both parental and tamoxifen-resistant breast cancer cells. Thioridazine induces phospholipid accumulation, triggering necroptosis through RIP signaling and MLKL-mediated membrane pore formation, confirmed via scanning electron microscopy.
Funding: SERB -CRG (2024-27)
https://doi.org/10.1039/D5MO00039D
Image : Necroptosis
cell and molecular biology, my research group aims to understand how cancer cells adapt to their microenvironmental stress and develop acquired drug resistance by studying organelle dynamics, metabolism, and signal transduction,
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